Humans synthesize and degrade several grams/day of hyaluronan (HA), which is a ubiquitous extracellular matrix component. HA degradation occurs via two clearance systems, one lymphatic (85%) and one hepatic (15%). Specific recycling HA receptors allow sinusoidal liver endothelial cells to endocytosis and degrade HA efficiently, thereby keeping blood HA levels low. HA levels are elevated in many diseases including rheumatoid arthritis, some cancers and liver cirrhoses, psoriasis, and progressive systemic sclerosis. The relationship between HA metabolism and aging has not yet been investigated. In the accelerated aging syndromes, Werner's and progeria, serum and urine HA levels are dramatically increased. Progressively elevated blood and urine HA levels also occur normally as humans age. Elevated blood or lymph HA levels may increase the risk of thromboembolic diseases during aging, since HA can increase blood viscosity and stimulate fibrin clot formation in vitro. HA modifies the behavior of many cells including those involved in the immune response. Our central hypothesis is that age-related changes in extracellular HA levels in blood and/or lymph can alter important cellular functions. The declines in some differentiated cellular functions that occur with age, such as reduced immunocompetence, may be due to changes in HA levels to which cells are exposed. Our long term goals are to understand how the body controls blood and lymph HA levels and to elucidate the role of HA metabolism in aging. Our specific aims will use 3, 18 and 30 month rats to determine the effects of aging on: (i) HA levels in lymph and serum determined with a sensitive radio-competition assay; (ii) the clearance of HA by perfused liver; (iii) the ability of lymph nodes to metabolize HA, and; (iv) the ability of HA to modulate the lipopolysaccharide-induced mitogenic response of spleen lymphocytes and the ability of these cells to bind or metabolize HA. We will assess age-related changes in the hepatic HA clearance system by determining the ability of perfused liver in situ to remove and degrade low MW125I-HA or high MW3H-HA. Age-related changes in lymphatic HA clearance will be assessed in isolated lymph nodes by measuring the levels of HA, HA-binding proteins or receptors and hyaluronidase. These studies will, for the first time, allow us to construct an overview of HA metabolism in the whole animal and how those processes change with age.